The present invention relates to new compounds from natural sources which are useful in the field of pharmaceuticals and inhibit the proliferation of tumor cells or viruses and exhibit antitumor or anti-viral effects, the process for preparing the compounds, their uses, and the cells for producing the compounds.
More particularly, the present invention relates to the culture products of the cell line derived from human placenta deciduae, typically CD57-positive, HLA.DR-strongly positive human natural suppressor (NS) cells xe2x80x9cCD57+HLA-DRbrightNS cell line (TTK-1)xe2x80x9d (referred to hereinafter as xe2x80x9cNS cellsxe2x80x9d) which have been further cloned from TTK-1 cells, the process for producing the culture products, their uses, and the NS cells.
In the field of chemical therapy of cancer, clinical applications of a number of metabolic products of microorganisms such as Bleomycin and Adriamycin have been tried, and these products have been practically used in clinical stages.
However, the effects of these products are not always satisfactory on a variety of tumors, and the clinical applicabilities have become complicated as the resistance phenomena of tumoral cells against these pharmaceuticals have been clinically revealed [see the abstracts of the 47th General Meeting of NIPPON GAN GAKKAI, pp. 12-15 (1988)].
On the other hand, it has been clarified that the maternal immune reaction to fetus is primarily controlled by decidua, and a large number of cellular groups belonging to large granular lymphocyte (LGL) with an NK cell marker have been accumulated at the decidual layer of mammals including human being of initial pregnancy [Mori, T. et Attachment A al., Immunomolecular mechanism in mammalian implantation. Endocrine. J., 41 (Suppl.): S17].
It has been recognized that the NS cell belonging to LGL is a cell group distinguished from immune T cell, B cell or macrophage, since it possesses a receptor to WGA lectin in mice and a sugar chain marker of CD57 in human beings.
It has been described that the NS cell also possesses a function for suppressing the division of cancer cells because of its function to potently suppressing the lymphocyte division reactions such as the division reaction of lymphocyte by mitogen MHC-non-restrictively or mixed lymphocyte reaction (Tilden et al., J. Immunol., 130, 1171).
However, a protein of the TGF-xcex2 family and a lipid-like material having a molecular weight of below 10,000 have been described as regards the causal factor managing the immunosuppressive effect on the cancer cell proliferation suppressive effect of the NS cell (Clark et al., J. Immunol., 144, 3008, and Mortari et al., J. Immunol., 144, 3037), but the exact structure or function of the NS cell remains ambiguous up to now and has been desired to be elucidated.
Conventional compounds having a chemical structure similar to the compound of the present invention and exerting anti-tumoral and/or anti-viral effects include fluorouracil (U.S. Pat. Nos. 2,802,005 and 2,885,396, doxifluridine (U.S. Pat. No. 4,071,680, Tegafur (GB Patent No. 1,168,391), Zidovudine; AZT (German Patent No. 3,608,606), Didanosine; ddI) (EP Laid-Open Publication No. 206497), and the like.
However, these anti-tumor agents and anti-virus agents of nucleic acid type not only are effective on limited kinds of tumor cells or viruses, but also act on normal human cell, so that these agents have high toxicities and become an object of public concern.
The present invention has been conducted in view of such problems in prior art, and the object of the present invention consists in searching for a substance in human cell metabolites having an efficacy against cancers, viruses and the like on which conventional anti-tumor agents and anti-virus agents exhibit only-insufficient effects, and providing a material which has carcinostatic effect on various resistant cancers and anti-virus effect as well as a reduced side effect such that normal human cells will not be impaired.
The present inventors have conducted earnest researches in order to accomplish the object and, as a result, have found that NS cell line induces the cell death of K562, Molt4, U937, BeWo, GCIY human cancer cells due to apoptosis, suppress the cytokinesis of cancer cells, and also found the nucleic acid type substances (referred to as AIF) which is secreted by the cell line and induces the cancer cell death due to apoptosis, and have isolated and purified the substances to determine the structures thereof. The inventors have believed that these substances can be developed and applied as a natural type carcinostatic agent and anti-virus agent as well as a pharmaceutical based on the quite new idea and having fewer side-effects.
The present inventors have cultured the NS cell having the ability for producing the compound of the formula (1) and derived from human placental decidua, collected the compound of the formula (1) from the culture fluid (supernatant and cells, especially supernatant), converted it into a pharmaceutically acceptable salt, if necessary, to obtain the compound represented by the formula (1) 
wherein
R1 represents the group 
R2 represents a hydrogen atom, a hydroxy group or a methoxy group,
or a pharmaceutically acceptable salt thereof, and found that the compound of the formula (1) or a pharmaceutically acceptable salt thereof induces the human cancer cell death due to apoptosis, suppresses the proliferation of cancer cells, and exhibits anti-tumor effect or anti-virus effect. The present invention has been thus accomplished.
That is to say, the present invention relates to the anti-tumor or anti-virus substance represented by the above described formula (1), wherein R1 and R2 have the same meanings. as defined above, or a pharmaceutically acceptable salt thereof, the process for preparing the same, a pharmaceutical containing the anti-tumor or anti-virus substance represented by the above described formula (1) or a pharmaceutically acceptable salt thereof as an effective ingredient, the use of the above described compound to the preparation of a pharmaceutical and therapy, and the CD57 positive, HLA.DR strongly positive NS cell derived from human placental decidua.